Project Summary The long term goal of this study is to elucidate the role of retrograde signaling and cell-cell interactions in the central nervous system (CNS) following peripheral axon injury. In particular we will focus on the plasticity that occurs in spinal cord oligodendrocyte (OL) lineage cells following injury of peripherally located sympathetic preganglionic axons. Following the transection of preganglionic axons in the cervical sympathetic trunk (CST), we observe robust region-specific increases in spinal cord oligodendrocyte progenitor cells (OPCs) and OLs that express full length TrkB, the cognate receptor for brain derived neurotrophic factor (BDNF). This plasticity is localized to only the region of the injured preganglionic neurons in the upper thoracic spinal cord. In Aim 1 we will test the hypothesis that the plasticity in OL lineage cells observed following peripheral axon injury is the result of proliferation and differentiation of OPCs. Because microglial cells in the spinal cord, which have been shown to influence the activities of OL lineage cells, show robust activation following the CST transection, we will test the hypothesis in Aim 2 that the presence of activated microglia is a requirement for OL cell plasticity. BDNF, which is increased in the spinal cord following CST transection, is known to regulate OL activities, and we observe an increase in TrkB OLs following CST transection, leading to the hypothesis in Aim 3 that TrkB and/or BDNF is necessary for OL plasticity to occur. We predict that the loss of TrkB signaling and/or BDNF following CST transection will severely impact OL plasticity. The mechanisms that regulate the process of OPC self-renewal and differentiation to become mature OLs are important because alterations in OL lineage cells underlie numerous neurological disorders including demyelinating disease, mood disorders, recovery following spinal cord injury, amyotrophic lateral sclerosis, and multiple sclerosis. Therefore, a better understanding of the many factors that regulate OL lineage cells has broad clinical implications. Use of our unique CST transection model allows for the examination of glial responses to neuronal injury in the absence of the secondary injury cascades initiated by spinal trauma. Only with this solid foundation can strategic therapeutic strategies be devised to augment cell survival and replacement following injury or disease in the adult nervous system.